GRK2-Targeted Knockdown as Therapy for Multiple System Atrophy.
Mov Disord
; 38(7): 1336-1340, 2023 07.
Article
en En
| MEDLINE
| ID: mdl-37093618
ABSTRACT
BACKGROUND:
Multiple system atrophy (MSA) is a sporadic adult-onset rare neurodegenerative synucleinopathy for which counteracting central nervous system insulin resistance bears the potential of being neuroprotective. G-protein-(heterotrimeric guanine nucleotide-binding protein)-coupled receptor kinase 2 (GRK2) is emerging as a physiologically relevant inhibitor of insulin signaling.OBJECTIVES:
We tested whether lowering brain GRK2 abundance may reverse insulin-resistance.METHODS:
We lowered brain GRK2 abundance through viral-mediated delivery of a GRK2-specific miRNA and quantified the reversion of a developing or an established insulin-resistant phenotype using the transgenic PLP-SYN mouse model of MSA.RESULTS:
Viral vector delivery of a GRK2 miRNA demonstrated a neuroprotective capacity when administered (1) in utero intracerebroventricularly in developing PLP-SYN mice and (2) intrastriatally in adult PLP-SYN mice. Decreased striatal GRK2 levels correlated in both designs with neuroprotection of the substantia nigra dopamine neurons, reduction in high-molecular-weight species of α-synuclein, and reduced insulin resistance.CONCLUSIONS:
These data support GRK2 as a potential therapeutic target in MSA. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.Palabras clave
Texto completo:
1
Base de datos:
MEDLINE
Asunto principal:
Resistencia a la Insulina
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Atrofia de Múltiples Sistemas
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MicroARNs
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Insulinas
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Trastornos del Movimiento
Límite:
Animals
Idioma:
En
Revista:
Mov Disord
Asunto de la revista:
NEUROLOGIA
Año:
2023
Tipo del documento:
Article
País de afiliación:
Francia